A patient suffering from a spinal cord injury is rapidly increasing due to the fact that the pace of economic development is accelerating. As a result, social medical expenses are increasing thereby causing serious economic losses. Most patients suffered from a spinal cord injury are young and involved in a lot of activities, so remarkable personal and national losses may be anticipated when taking their productivities of lifetimes into consideration. In addition, permanent losses of motor skill and sensory function due to a degeneration of nerve centre may degrade the quality of one's individual life, and may psychologically and economically affect on protectors who support patients, thereby causing severe social and cultural adverse reactions. Thus, a method of treating the spinal cord injury and a development of drug are sincerely required.
The spinal cord injury causes sudden paralysis thereby causing a functional impairment of various parts so that it has a risk factor that may cause a variety of complications. The neuropathy does not limit to a nerve knot that is directly pressed, but is generated over widely nerve that is presented below a nerve knot. In addition, physiological functions that are damaged after a traumatic injury are not stopped as they are, but deteriorated worse and worse (el Masry W S, Short D J., 1997).
A study published in 1997 found that when a spinal cord injury is generated, an excitotoxicity neurotransmitter, a free radical, inflammatory mediators, and the like are generated so that apoptosis is induced. Recently, after revealing that an unsuitable environment for nerve regeneration is made due to a formation of glial scar (Liu X U et al., 1997, Fitch M T, Silver J., 2008), a lot of researchers are focusing on developing a treatment method that can help a recovery of a nerve function and minimize a neuropathy. However, there is only a methylprednisolone treatment that acts to decrease a damage of a nervous tissue within 24 hours after damaging, that is, in an acute phase, in which the methylprednisolone treatment is recognized as a treatment of a spinal cord injury through a clinical test (Bracken et al., 1990). However, the curative power of the methylprednisolone treatment is insignificant and its utility is still highly controversial (Schwab et al., 1996). Therefore, scientists all over the world studied tissue and cell transplants, an injection of neurotrophin, a production of neurotrophin using gene therapy, a microsurgery, an injection of a combination, and the like by actively progressing a study about all types of agents for a neuro-protective therapy. That is, until now, there remain no effective treatments to improve neurological outcomes following SCI. Accordingly, a development of drug for recovering the spinal cord injury is more urgently needed.
The spinal cord injury is mainly caused by pressing a spinal cord through a displacement of spine due to a traumatic injury. A necrosis is caused immediately after damaging along with a mechanical primary damage, apoptosis of oligodendrocyte in the white matter and a neuronal cell of a grey matter is caused due to a slowly generated apoptosis, and a demyelination of axon is caused thereby ultimately generating a permanent functional disorder. Considering its pathophysiologic analysis, main causes of apoptosis are known as the following factors: an excitotoxicity due to a large amount of glutamate initially isolated in a damaged site after damage of spinal cord injury; an oxidative stress due to an active oxygen (ROS); ATP depletion; an ischemia due to an hypoxia environment, and then; an inflammation due to inflammatory mediators, such as iNOS, or proinflammatory cytokines, such as TNF-α, IL-1β, and the like; and the like (Lu et al., 2000, Kapoor et al., 2003). Among these factors, the inflammatory reaction lasts through a long period as well as at the very beginning. Especially, apoptosis that slowly progresses or an inflammatory reaction due to microglia in axon degeneration is pathologic property that is commonly exhibited in most nerve diseases as well as a spinal cord injury so that it is known that its regulation is important to prevent an expansion of disease of a nerve system (Beattie, 2004).
A senile dementia, which is known as the global disease giving pains to many people, is one of central nervous system diseases. There are various factors causing the senile dementia, and about 50% of the diseases is Alzheimer-type dementia, and 20˜300 of the diseases is a vascular dementia, a alcoholic dementia, a dementia due to Parkinson's disease, and the like. In addition, Parkinson's disease that is a representative degenerative cerebropathia is often accompanied by Alzheimer's disease or an amyotrophic lateral sclerosis thereby suggesting a common pathologic mechanism of degenerative brain disease. Considering a pathologic mechanism of nervous system diseases that are commonly generated, there are an abnormal accumulation of the most degenerative nervous diseases, such as a senile dementia, Parkinson's disease, a bovine spongiform encephalopathy, Huntington's disease, an amyotrophic lateral sclerosis and the like, and protein condensation and deposition therefrom. The deposits induce an oxidative stress in a nerve cell and decrease a mitochondria function thereby inducing apoptosis, and also the destruction product generated for this reason acts as an immunity-inflammation stimulating factor thereby activating a complement pathway and a microglia, and an inflammatory reaction is accelerated by a positive feedback to stimulate a degeneration change (McGeer et al., 1995, Kohutnicka et al., 1998, Alexianu et al., 2001).
Meanwhile, it is known that all sorts of central nervous diseases are involved in apoptosis of nerve cell. For example, cells having a part reflecting a light and shade line as a progressive process of ischemic injury for a stroke will die for a period of weeks due to apoptosis (Lo et al., 2003). In addition, apoptosis breaks out at a dopamine nerve cell that is presented at a brain substantia nigraas due to reasons, such as an oxidative stress, a mitochondria dysfunction, a death receptor, and the like, for Parkinson's disease that is a degenerative central nervous system disease (Tansey et al., 2007). And also, apoptosis breaks out due to an amyloid beta protein for Alzheimer's disease (Tesco et al., 2003). Accordingly, it was revealed that apoptosis is the main cause of an amyotrophic lateral sclerosis that selectively loss of motor neuron, Huntington's disease that induces apoptosis by a fatal genetic disorder, and all sorts of mental diseases (Mattson et al., 2008). It can be expected from the above results that a development of drug that can prevent apoptosis is essential to treating Parkinson's disease, Alzheimer's disease, an amyotrophic lateral sclerosis, Hungtington's disease, which are degenerative central nervous system diseases, a depressive disorder, an epilepsy, and the like, which have similar mechanisms as a spinal cord injury and a stroke, as well as a spinal cord injury and a stroke, and also marketability thereof is enormous.
Meanwhile, the most important measurement of recovery from a spinal cord injury may be a result of observing the behavioral change thereof, and thus it may be based on BBB locomotor rating scale measuring a loss and recovery of motor skill shown after a spinal cord injury (Basso et al., 1995).
Substance P (hereinafter, also called as to ‘SP’) is a peptide consisting of 11 amino acids, and widely distributed at a nervous tissue (Kramer et al., 1998) and various organs (skin, salivary glands, lung, pancreas, kidney, bladder, prostate) (Kohlmann et al., 1997, Rupniak and Kramer., 1999). Especially, Substance P is generated at a dorsal root ganglion, and largely distributed at a posterior column of spinal cord, and Substance P is also found at a peripheral process and a central C fiber in a peripheral nervous system (Radhakrishnan and Henry., 1995, Henry., 1993, Vaught 1988). A noxious stimulus occurs by involving in a pain as a physiological function thereby secreting Substance P from primary afferent terminals affecting a neurokinin 1 receptor, and then activating 2nd messenger to induce influx of calcium ions. It is known that an increase of calcium ion influx accelerates a generation of nitric oxide, and the resulting nitric oxide increases release of Substance P by a feedback thereby forming a hypersensitization through signaling pathways of Substance P (Radhakrishnan and Henry., 1995, Chatani et al., 1995). The mechanism involved in a pain largely limits possibility of developing a drug treating agent of Substance P in central nervous system injury and degenerative diseases by a researcher.
Besides this, it is reported and known that Substance P is involved in inducing various inflammatory reactions in a peripheral nervous system and also in treating an injury by increasing penetrability of endotheliocyte and vasodilation (Matthay M A and Ware L, 2004). Accordingly, the present inventors had identified that an administration of Substance P accelerates an injury treatment after injuring in a cornea injury model.
Since then, the present inventors found that Substance P is involved in killing a central nervous cell that is generated after a spinal cord injury, and contributes greatly to a recovery of motor skill so that we could complete the present invention through repeated researches.